As an undergraduate student of biology in Tübingen I developed a strong interest in how cells function. Based on this I decided to pursue my PhD in Prof. Olaf Stemmann’s lab at the Max-Planck-Institute of Biochemistry in Munich, working on the function and regulation of the protease separase in mitosis and meiosis. Separase induces sister chromatid segregation in anaphase by cleaving cohesin, the “glue” that holds sister chromatids together. Canonically, separase is kept inactive before anaphase by binding its inhibitor, securin. We discovered an additional, securin-independent, mechanism of separase inhibition: high Cdk1 activity leads to phosphorylation of separase (Gorr et al. Mol Cell 2005). This enables Cyclin B/Cdk1 to form contacts with separase (Boos et al. JBC 2008), leading to mutual inhibition of the protease and the kinase. This work provided an explanation how cells without securin still manage timely activation of separase and sister chromatid separation. It also showed how separase can help down-regulate Cdk1 activity, thus facilitating in mouse oocytes the transition of meiosis I to meiosis II.

Based on my interest in fundamental cell biological questions I then chose to do a postdoc in the lab of Dr John Diffley at the CRUK London Research Institute to work on how cells duplicate their genome by DNA replication before they can separate their chromosomes in mitosis. I could make two major contributions to the field of mammalian replication: I established the protein Treslin as the functional vertebrate orthologue of yeast Sld3, demonstrating it is a hub for the regulation of replication (Boos et al. Cur Biol 2011). My second contribution (Boos et al. Science 2013) was to identify an entirely novel vertebrate-specific replication initiation factor, the Treslin-interacting MTBP protein (Mdm2 binding protein), showing that, despite conservation of fundamental replication mechanisms with yeast, significant differences exist in humans.
I described that Treslin, like yeast Sld3, is a point of convergent regulation by the cell cycle and the DNA damage response pathway. It couples the initiation of DNA replication to the cell cycle by its cell cycle-specific association with the essential replication factor TopBP1. Upon exposure of cells to DNA-damaging chemicals this interaction becomes inhibited, suppressing excessive replication under conditions that favour genetic mutations. The MTBP protein had previously been shown to have strong links to cancer, possibly mediated via the activation of the Mdm2 ubiquitin ligase. MTBP had also been found to be essential in early mouse embryos. However, genetic experiments had indicated that MTBP’s suggested role in regulating Mdm2 cannot be the reason it is essential in mice. My work offers a resolution of this conundrum by showing that the binding of MTBP to Treslin is essential for the initiation of replication. How MTBP is linked to tumour development remains an intriguing question for future research.

In my own lab in Essen I would like to build on my postdoc work in order to find out how DNA replication occurs in vertebrate cells, how regulation of replication integrates it into the complex cellular processes, and mechanisms of DNA replication contribute to genetic instability and cancer formation.